Abstract

Neurogenesis is sustained throughout life in the mammalian brain, supporting
hippocampus-dependent learning and memory. Its permanent alteration by
status epilepticus (SE) is associated with learning and cognitive impairments.
The mechanisms underlying the initiation of altered neurogenesis after SE are
not understood. GFAP-positive radial glia (RG) -like cells proliferate early after
SE, but their proliferation dynamics and signaling are largely unclear. We have
previously reported a polarized distribution of AMPA receptors (AMPARs) on
RG-like cells in-vivo and postulated that these may signal their proliferation.
Here, we examined the acute effects of kainate on hippocampal precursor cells
in-vitro and in kainate-induced SE on proliferating and quiescent clones of
BrdU pre-labelled hippocampal precursors in-vivo.
In-vitro, we found that 5 μM kainate shortened the cell cycle time of RG-like
cells via AMPAR activation and accelerated cell cycle re-entry of their progeny.
It also shifted their fate choice expanding the population of RG-like cells and
reducing the population of downstream amplifying neural progenitors. Kainate
enhanced the survival of all precursor cell subtypes. Pharmacologically,
kainate’s proliferative and survival effects were abolished by AMPAR
blockade. Functional AMPAR expression was confirmed on RG-like cells invitro.
In agreement with these observations, kainate/seizures enhanced the
proliferation and expansion predominantly of constitutively cycling RG-like cell clones in-vivo. Our results identify AMPARs as key potential players in
initiating the proliferation of dentate RG-like cells and unravel a possible
receptor target for modifying the radial glia-like cell response to SE.